1. Field of the Invention
The present invention relates to an antibody which specifically binds to an amyloid-β (hereinafter, also referred to as Aβ) protein oligomer and use thereof.
2. Brief Description of the Background Art
It is considered based on various pieces of evidence that the decline in memory in Alzheimer's disease (hereinafter, referred to as AD) is caused as a result of synapse dysfunction due to soluble oligomers of amyloid-β protein (hereinafter, amyloid-β protein is also referred to as Aβ, and amyloid-β protein oligomer is also referred to as Aβ oligomer) (Non-Patent Documents 1 and 2).
Accordingly, there is a possibility that excessive accumulation or deposition of Aβ oligomers in a brain triggers a series of pathological cascades which may cause AD. This indicates a possibility that medical treatment targeting Aβ oligomers may be effective in delaying or preventing the onset and the progression in the disease stage of AD.
However, the knowledge relating to the neurodegeneration caused by a molecule responsible for this amyloid-cascade hypothesis as its core factor, particularly by Aβ oligomers was mainly demonstrated in experiments in vitro (Non-Patent Document 3) and was not directly demonstrated in vivo.
Since the structures specific to Aβ oligomers have not been studied in the in vivo experiments which have been reported before (Non-Patent Document 4), synaptic toxicity due to endogenous Aβ oligomers has not been clarified.
In addition, although studies have been carried out in various AD model mice, neuronal toxicity of Aβ oligomers in the brain of an AD patient has not yet been revealed.
Furthermore, it has not yet been established why the formation of neurofibrillary tangle (hereinafter, simply referred to as NFT) and the loss of nerve cell occurs prior to pathogenesis of neuritic plaque in the human entorhinal cortex and how Aβ oligomers relate to these tissue degeneration and dysfunctions.
As antibodies against Aβ oligomers, anti-Aβ oligomer mouse monoclonal antibody NAB61 (Non-Patent Document 4), 1A9, 2C3, E12, 1C10, and 4D3 (Patent Document 1) are known.
It is known that generally, when a non-human antibody such as a mouse antibody is administered to human, it is recognized as a foreign substance so that a human antibody for mouse antibody (human anti mouse antibody: HAMA) is induced in the human body. It is known that HAMA reacts with the administered mouse antibody to thereby induce side effects (Non-patent Documents 5 to 8), quickens disappearance of the mouse antibody from the body (Non-patent Documents 6, 9 and 10) and decreases therapeutic effect of the mouse antibody (Non-patent Documents 11 and 12).
In order to solve these problems, attempts have been made to prepare a recombinant antibody such as a human chimeric antibody and a humanized antibody from a non-human antibody using genetic recombination techniques.
A human chimeric antibody, a humanized antibody and the like have various advantages in clinical application to human in comparison with a non-human antibody such as a mouse antibody. For example, it has been reported that its immunogenicity was decreased and its blood half-life was prolonged in a test using monkey, compared to a mouse antibody (Non-patent Document 13).
That is, since a human chimeric antibody, a humanized antibody and the like cause fewer side effects in human than non-human antibodies, it is expected that its therapeutic effect is sustained for a prolonged time.
Also, since a recombinant antibody such as a human chimeric antibody, a humanized antibody and a human antibody is prepared using recombination techniques, it can be prepared as various forms of molecules.
For example, γ1 subclass can be used as a heavy chain (hereinafter referred to as “H chain”) constant region (hereinafter referred to as “C region”) of a human antibody (H chain C region is referred to as “CH”) to produce a recombinant antibody having high effector functions such as antibody-dependent cellular cytotoxicity (hereinafter referred to as “ADCC activity”). In addition, γ2 or γ4 subclass can be used as a heavy chain to produce a recombinant antibody which has decreased effector function and is expected to prolong of its blood half life in comparison with mouse antibodies (Non-patent Document 14).
Particularly, since cytotoxic activities such as complement-dependent cytotoxicity (hereinafter referred to as “CDC activity”) and ADCC activity via the Fc region (the region after the antibody heavy chain hinge region) of an antibody are important for the therapeutic efficacy, a human chimeric antibody, a humanized antibody or a human antibody is preferred compared to a non-human animal antibody such as a mouse antibody (Non-patent Documents 15 and 16).
In addition, with recent advance in protein engineering and genetic engineering, a recombinant antibody can also be prepared as an antibody fragment having small molecular weight, such as Fab, Fab′, F(ab′)2, a single chain antibody (hereinafter referred to as “scFv”) (Non-patent Document 17), a dimerized V region fragment (hereinafter referred to as “Diabody”) (Non-patent Document 18), a disulfide stabilized V region fragment (hereinafter referred to as “dsFv”) (Non-patent Document 19), and a peptide comprising a CDR (Non-patent Document 20). These antibody fragments have a greater advantage in transfer to target tissues than whole antibody molecules (Non-patent Document 21).
The above-mentioned facts indicate that a human chimeric antibody, a humanized antibody, a human antibody or an antibody fragment thereof is more preferable as the antibody to be used for the clinical application to human than a non-human animal antibody such as a mouse antibody.